Mechanism Of Action
Vorinostat inhibits the enzymatic activity of histone deacetylases HDAC1, HDAC2 and HDAC3 (Class I) and HDAC6 (Class II) at nanomolar concentrations (IC50<86 nM). These enzymes catalyze the removal of acetyl groups from the lysine residues of proteins, including histones and transcription factors. In some cancer cells, there is an overexpression of HDACs, or an aberrant recruitment of HDACs to oncogenic transcription factors causing hypoacetylation of core nucleosomal histones. Hypoacetylation of histones is associated with a condensed chromatin structure and repression of gene transcription. Inhibition of HDAC activity allows for the accumulation of acetyl groups on the histone lysine residues resulting in an open chromatin structure and transcriptional activation. In vitro, vorinostat causes the accumulation of acetylated histones and induces cell cycle arrest and/or apoptosis of some transformed cells. The mechanism of the antineoplastic effect of vorinostat has not been fully characterized.
The pharmacokinetics of vorinostat were evaluated in 23 patients with relapsed or refractory advanced cancer. After oral administration of a single 400-mg dose of vorinostat with a high-fat meal, the mean ± standard deviation area under the curve (AUC) and peak serum concentration (Cmax) and the median (range) time to maximum concentration (Tmax) were 5.5±1.8 µM●hr, 1.2±0.62 µM and 4 (2-10) hours, respectively.
In the fasted state, oral administration of a single 400-mg dose of vorinostat resulted in a mean AUC and Cmax and median Tmax of 4.2±1.9 µM●hr and 1.2±0.35 µM and 1.5 (0.5-10) hours, respectively. Therefore, oral administration of vorinostat with a high-fat meal resulted in an increase (33%) in the extent of absorption and a modest decrease in the rate of absorption (Tmax delayed 2.5 hours) compared to the fasted state. However, these small effects are not expected to be clinically meaningful. In clinical trials of patients with CTCL, vorinostat was taken with food.
At steady state in the fed-state, oral administration of multiple 400-mg doses of vorinostat resulted in a mean AUC and Cmax and a median Tmax of 6.0±2.0 µM●hr, 1.2±0.53 µM and 4 (0.5-14) hours, respectively.
Vorinostat is approximately 71% bound to human plasma proteins over the range of concentrations of 0.5 to 50 µg/mL.
The major pathways of vorinostat metabolism involve glucuronidation and hydrolysis followed by β-oxidation. Human serum levels of two metabolites, O -glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid were measured. Both metabolites are pharmacologically inactive. Compared to vorinostat, the mean steady state serum exposures in humans of the O -glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid were 4-fold and 13-fold higher, respectively.
In vitro studies using human liver microsomes indicate negligible biotransformation by cytochromes P450 (CYP).
Vorinostat is eliminated predominantly through metabolism with less than 1% of the dose recovered as unchanged drug in urine, indicating that renal excretion does not play a role in the elimination of vorinostat. The mean urinary recovery of two pharmacologically inactive metabolites at steady state was 16±5.8% of vorinostat dose as the O‑ glucuronide of vorinostat, and 36±8.6% of vorinostat dose as 4-anilino-4-oxobutanoic acid. Total urinary recovery of vorinostat and these two metabolites averaged 52±13.3% of vorinostat dose. The mean terminal half-life (t½) was ~2.0 hours for both vorinostat and the O -glucuronide metabolite, while that of the 4-anilino-4-oxobutanoic acid metabolite was 11 hours.
Based upon an exploratory analysis of limited data, gender, race and age do not appear to have meaningful effects on the pharmacokinetics of vorinostat.
Vorinostat was not evaluated in patients <18 years of age.
Vorinostat was not evaluated in patients with hepatic impairment. [See Use in Specific Populations.]
Vorinostat was not evaluated in patients with renal impairment. However, renal excretion does not play a role in the elimination of vorinostat. [See Use in Specific Populations.]
Pharmacokinetic effects of vorinostat with other agents
Vorinostat is not an inhibitor of CYP drug metabolizing enzymes in human liver microsomes at steady state Cmax of the 400 mg dose (Cmax of 1.2 µM vs IC50 of >75 µM). Gene expression studies in human hepatocytes detected some potential for suppression of CYP2C9 and CYP3A4 activities by vorinostat at concentrations higher (≥10 µM) than pharmacologically relevant. Thus, vorinostat is not expected to affect the pharmacokinetics of other agents. As vorinostat is not eliminated via the CYP pathways, it is anticipated that vorinostat will not be subject to drug-drug interactions when co-administered with drugs that are known CYP inhibitors or inducers. However, no formal clinical studies have been conducted to evaluate drug interactions with vorinostat.
In vitro studies indicate that vorinostat is not a substrate of human P-glycoprotein (P-gp). In addition, vorinostat has no inhibitory effect on human P-gp-mediated transport of vinblastine (a marker P-gp substrate) at concentrations of up to 100 μM. Thus, vorinostat is not likely to inhibit P-gp at the pharmacologically relevant serum concentration of 2 μM (Cmax) in humans.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenicity studies have not been performed with vorinostat.
Vorinostat was mutagenic in vitro in the bacterial reverse mutation assays (Ames test), caused chromosomal aberrations in vitro in Chinese hamster ovary (CHO) cells and increased the incidence of micro-nucleated erythrocytes when administered to mice (Mouse Micronucleus Assay).
Effects on the female reproductive system were identified in the oral fertility study when females were dosed for 14 days prior to mating through gestational day 7. Doses of 15, 50 and 150 mg/kg/day to rats resulted in approximate exposures of 0.15, 0.36 and 0.70 times the expected clinical exposure based on AUC. Dose dependent increases in corpora lutea were noted at ≥15 mg/kg/day, which resulted in increased peri-implantation losses were noted at ≥50 mg/kg/day. At 150 mg/kg/day, there were increases in the incidences of dead fetuses and in resorptions.
No effects on reproductive performance were observed in male rats dosed (20, 50, 150 mg/kg/day; approximate exposures of 0.15, 0.36 and 0.70 times the expected clinical exposure based on AUC), for 70 days prior to mating with untreated females. [See Warnings and Precautions.]